Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve

fibres in inflammatory bowel disease and functional effects in

cultured neurons

Uma Anand Yiangos Yiangou, Ayesha Akbar, Tom Quick, Anthony MacQuillan,
Mike Fox, Marco Sinisi, Yuri E. Korchev, Ben Jones, Steve R. Bloom,
Praveen Anand
INTRODUCTION

 Inflammatory bowel disease (IBD) is an idiopathic chronic, inflammatory disorder

of the intestinal tract, afflicting 1 in 400 individuals in the UK and compromising
their quality of life.

 GLP-1 that induces satiety is considered to significant weight loss prior to diagnosis
(>5% BMI loss) was observed in subjects with Crohn's Disease and subjects with
Ulcerative colitis.

 In This study found increased levels of GLP-1R and sensory/nociceptor innervation

in IBD gut tissues, and presence of GLP-1R in human DRG neurons.
Materials and methods
 Tissues
from Colonoscopic, rectosigmoid biopsies were collected from patients with IBD
 Cell transfection
 Immunohistochemistry and analysis
 Human DRG neuron cultures
 Adult rat DRG neuron cultures
 Effect on neurite outgrowth
 Immunostaining
 Calcium imaging
RESULTS
Colon biopsies

 GLP-1R fibres were seen throughout the mucosa of control sigmoid colon biopsy
specimens, and appeared greater in the IBD group.

 Image analysis of GLP-1R immunoreactive fibres in sigmoid colon biopsies showed

a significant increase in IBD

 CGRP fibres were also found in the mucosa of colonic biopsies (Fig 3). Counts of
CGRP immunoreactive fibres in sigmoid colon biopsies (expressed as fibres /mm2),
also showed a significant increase in IBD
DISCUSSIONS
 CGRP and GLP-1R-like immunoreactivity is expressed by the innervation of
human colon and increased in biopsies.

 GLP-1R may participate in modulating gut motility, rather than pain signalling.

 GLP-1 regulates appetite, elevated levels in IBD may contribute to the loss of
appetite.

 Chronically elevated levels of GLP-1 in IBD may provide a neurotrophic effect,

resulting in increased nerve fibre density of GLP-1R expressing nerve fibres.
Most patients in the study all had gastrointestinal symptoms and gut dysmotility
DISCUSSIONS
 nociceptive capsaicin / heat pain receptor TRPV1 was not affected by acute
application of these gut hormones, indicating that the GLP-1R may not
participate in noxious signalling involving TRPV1.

 Enhanced ATP signalling in the presence of Exendin-4 in the human DRG

neurons, and in rodent neurons, suggest that GLP-1R may participate in
modulating gut motility, rather than pain signalling
CONCLUSIONS
 GLP-1R is expressed in nerves innervating the intestine, and is significantly
increased in bowel biopsies from IBD patients.

 The incretin hormones promote neurite outgrowth in cultured DRG neurons, and
may underlie the observation of increased nerve fibres in IBD.

 While ATP signalling was enhanced, capsaicin sensitivity was not affected by
acute application of exendin-4 or oxyntomodulin in sensory neurons.

 GLP-1R innervation may be involved in IBD bowel pathophysiology and

afferent signalling, and potentially provide a peripheral therapeutic target for
satiety and weight loss.
THANK YOU